Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity

Abstract

Searching for prospective vanadium-based drugs for the treatment of Chagas disease, a new series of heteroleptic [VIVO(L-2H)(NN)] compounds was developed by including the lipophilic 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) NN ligand and seven tridentate salicylaldehyde semicarbazone derivatives (L1–L7). The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligand is bidentate bound through both nitrogen donor atoms in an axial–equatorial mode. The EPR and 51V-NMR spectra of aerated solutions at room temperature indicate that the compounds are stable to hydrolysis and that no significant oxidation of VIV to VV takes place at least in 24h. The complexes are more active in vitro against Trypanosoma cruzi, the parasite responsible for Chagas disease, than the reference drug Nifurtimox and most of them are more active than previously reported [VIVO(L-2H)(NN)] complexes of other NN co-ligands. Selectivity towards the parasite was analyzed using J-774 murine macrophages as mammalian cell model. Due to both, high activity and high selectivity, L2, L4, L5 and L7 complexes could be considered new hits for further drug development. Lipophilicity probably plays a relevant role in the bioactivity of the new compounds. The [VIVO(L-2H)(NN)] compounds were designed aiming DNA as potential molecular target. Therefore, the novel L1–L7 tmp complexes were screened by computational modeling, comparing their DNA-binding features with those of previously reported [VIVO(L-2H)(NN)] compounds with different NN co-ligands. Whereas all the complexes interact well with DNA, with binding modes and strength tuned in different extents by the NN and semicarbazone co-ligands, molecular docking suggests that the observed anti-T. cruzi activity cannot be explained upon DNA intercalation as the sole mechanism of action.